Selective Inhibitor of eIF2[alpha] Dephosphorylation Protects Cells from ER Stress

Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a sel...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2005, Vol.307 (5711), p.935-939
Main Authors: Boyce, Michael, Bryant, Kevin F, Jousse, Céline, Long, Kai, Harding, Heather P, Scheuner, Donalyn, Kaufman, Randal J, Ma, Dawei, Coen, Donald M, Ron, David, Yuan, Junying
Format: Article
Language:English
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Summary:Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit [alpha] (eIF2[alpha]). Salubrinal also blocks eIF2[alpha] dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2[alpha] dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.
ISSN:0036-8075
1095-9203